Absolute configuration of anti-HIV-1 agent (-)-concentricolide: Total synthesis of (+)-(R)-concentricolide

Article abstract of DOI:10.1021/jo2004132

The first enantioselective total synthesis of (+)-(R)-concentricolide, the enantiomer of an anti-HIV-1 agent isolated from Daldinia concentrica, from 2-iodophenol in 7 steps reveals the (S)-configuration for the natural form of the furanophthalide. The key features include an anionic ortho-Fries rearrangement to furnish 3-iodosalicylamide, facile construction of the benzofuran system employing the tandem Sonogashira coupling annulation reaction, directed ortho metalation to introduce a propanoyl group, as well as CBS reduction, establishing the stereocenter enantioselectively.

Full text of DOI:10.1021/jo2004132

NOTE
pubs.acs.org/joc
Absolute Configuration of Anti-HIV-1 Agent (ꢀ)-Concentricolide:
Total Synthesis of (þ)-(R)-Concentricolide†
Chih-Wei Chang and Rong-Jie Chein*
Institute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan 11529
S Supporting Information
b
ABSTRACT: The first enantioselective total synthesis of (þ)-(R)-concentrico-
lide, the enantiomer of an anti-HIV-1 agent isolated from Daldinia concentrica,
from 2-iodophenol in 7 steps reveals the (S)-configuration for the natural form of
the furanophthalide. The key features include an anionic ortho-Fries rearrange-
ment to furnish 3-iodosalicylamide, facile construction of the benzofuran system
employing the tandem Sonogashira coupling annulation reaction, directed ortho
metalation to introduce a propanoyl group, as well as CBS reduction, establishing
the stereocenter enantioselectively.
Table 1. Optimization of the Tandem Sonogashira Coupling
he devastating AIDS (Acquired Immunodeficiency Syn-
Annulation
T
drome) in humans is caused by HIV (Human Immunode-
ficiency Virus) that attacks and gradually destroys the CD4
T-helper cells of the immune system. Depletion of the relevant
T-lymphocytes predisposes invasion of opportunistic pathogens
as well as incurrence of neurologic and neoplastic diseases from
which death follows. Current therapy of AIDS targets primarily at
the intervention of viral replication and entry into T cell. To this
end, drugs for inhibiting reverse transcriptase, protease, inte-
grase, viral absorption, viral uncoating, and viral fusion have been
developed and some combinations are employed clinically.1,2
There have been active quests for anti-HIV agents from plant
sources.3 Constituents belonging to the alkaloid, coumarin,
flavonoid, lignan, phenolic, quinone, saponin, terpenoid/sterol,
xanthone, carbohydrate, peptide, and protein families have been
identified. Several of them have proceeded to phase I or phase IIb
stage of drug development.4 As therapeutic agents are in urgent
demand due to the emergence and transmission of drug-resistant
variants, this search remains incessant to this day. Recently,
(ꢀ)-concentricolide, a fungal metabolite of the Ascomycete
Daldinia concentrica, was isolated (120 mg from 750 g of dried
fruiting bodies) and its in vitro anti-HIV-1 activity was noted
(EC50 0.31 μg/mL in the inhibition of HIV-1-induced cytopathic
effects; EC50 0.83 μg/mL in the blockage of syncytium formation
between HIV-1 infected cells and normal cells).5 Although there
have been a racemic synthesis6 via a DielsꢀAlder reaction of
furan-3-carbaldehyde and dihydrofuran-2(3H)-one and a discus-
sion on the assignment of the configuration of (ꢀ)-concentri-
colide by DFT calculation,7 the uncertainty of the absolute
structure still remains; moreover, this tricyclic compound being
the prototype of a new structural class deserves further study.
Herein we describe a synthesis of (þ)-concentricolide that also
serves to establish its absolute configuration.
temp, Pd(PPh3)2Cl2, CuI, time, products
entry sovlent
°C
mol %
mol %
h
5/6a yield, c %
1
CH3CN
90
100
90
5
10
10
1
10
20
20
2
96
96
70
2
1/4
1/7
85
85
83
80
88
2b toluene
3b CH3CN
>1/19
4/1
4
5
CH3CN
CH3CN
65
65
1
2
96
>1/19
a The product ratio of 5 and 6 was determined by 1H NMR. b A second
portion of 5 mol % of Pd(PPh3)2Cl2 and 10 mol % of CuI was added
after 48 h. c Yield of an inseparable mixture of 5 and 6.
ortho-Fries rearrangement.8 Treatment of 4 with trimethylsilylace-
tylene in the presence of 1 mol % of bis(triphenylphosphine)-
palladium(II) chloride and 2 mol % of cuprous iodide in triethyl-
amineꢀacetonitrile at 65 °C for 4 days gave benzofuran 6 in 88%
yield. Significantly, higher reaction temperature decreased the turn-
over number of the catalyst system for the annulation from
Sonogashira intermediate 5 to benzofuran 6 (Table 1 entries 1
and 2)9 and consequently much higher catalyst loading with
portionwise addition was required for the completion of the
tandem reaction (Table 1 entry 3). Benzofuran 6 was then
converted to a propanoyl derivative (7) by ortho-directed10
lithiation and N-methoxy-N-methylpropionamide in 76%
Our synthetic route started from commercially available 2-iodo-
phenol (2) (Scheme 1). The hydroxy group was carbamated to
afford 3 that was transformed into 3-iodosalicylamide 4 via anionic
Received: February 26, 2011
Published: April 04, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo2004132 J. Org. Chem. 2011, 76, 4154–4157
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Synthesis of (þ)-(R)-Concentricolidea
a Reagents and conditions: (a) K2CO3, N,N-diethylchloroformamide, CH3CN, reflux, 2 h; (b) LDA, THF, ꢀ60 °C; (c) trimethylsilylacetylene, Et3N,
Pd(PPh3)2Cl2 (1 mol %), CuI (2 mol %), CH3CN, 65 °C, 96 h; (d) TMEDA, t-BuLi, THF, ꢀ80 °C, 1.5 h; N-methoxy-N-methylpropionamide; (e)
(S)-B-nBu-CBS catalyst (0.5 equiv), BH3ꢀTHF, 0 °C; (f) KOAc, o-xylene, 130 °C, 1 h; (g) TBAF, AcOH, rt, 10 min.
Scheme 2. Preparation of (þ)-1a
a Reagents and conditions: (h) Br2, CH2Cl2, rt, 10 min; (i) Zn, AcOH, H2O, 100 °C, 1 h.
yield.11 This manipulation allowed us to gain access to a chiral
intermediate and hence optically active concentricolide, enabling
us to determine the absolute configuration of 1. Thus, upon
reduction of 7 by the CBS protocol12 the resulting rotamers13
were treated with potassium acetate in hot xylene without
purification to generate phthalide 8 in 86% yield with 80% ee.
Slightly to our disappointment, endeavors to further improve the
enantioselectivity of CBS reduction were not promising. This
would be attributed to the participation of the anilide group in
the pretransition state of the borane-CBS catalystꢀketone
assembly whose conformers interconvert sufficiently slowly
and erode the facial selectivity. After desilylation with tetrabuty-
lammonium fluoride buffered with acetic acid14 for the preven-
tion of the chirality loss, the final product (þ)-1 (Scheme 2) with
opposite optical rotation to the natural product was obtained in
86% yield ([R]25D þ26.1 (c 0.81, CH3OH)),5 of which structure
was confirmed by NMR,15 IR, mass spectra, and X-ray crystal-
lography. Remarkably, the absolute configuration (R) of (þ)-1
was assigned by the application of the mechanistic model of CBS
reduction as well as the X-ray diffraction analysis of its bromo
derivative 9, which was prepared from 8 by simple treatment with
bromine in methylene chloride at room temperature. Recrystalliza-
tion from ethyl acetateꢀhexane afforded 9 of >99% ee, mp
155ꢀ156 °C. Exposure of bromide 9 to 10 equiv of zinc powder
in acetic acid/water at 100 °C gave enantiopure (þ)-(R)-concen-
tricolide: >99% ee, mp 89ꢀ90 °C (petroleum ether/acetone);
mp 116ꢀ117 °C (ethyl acetate/hexane), [R]25 þ34.8 (c 0.48,
D
CH3OH). All data for (þ)-(R)-1 were in good agreement with
those reported by Liu et al. except optical rotation, which had been
confirmed several times in two different polarimeters.16
In summary, the efficient and expeditious synthesis of
(þ)-(R)-concentricolide was accomplished enantioselectively
in a linear sequence of 7 steps and an overall yield of 32% from
easily accessible starting materials. The absolute configuration of
the natural chiral form of concentricolide was affirmed as (S).
’ EXPERIMENTAL SECTION
O-(2-Iodophenyl)-N,N-diethylcarbamate (3):17 A mixture of
2-iodophenol (10.8 g, 49.1 mmol), K2CO3 (20.3 g, 147.3 mmol), and
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The Journal of Organic Chemistry
NOTE
N,N-diethylchloroformamide (7.5 mL, 58.9 mmol) in CH3CN (100 mL,
ACS grade for direct use) was heated to reflux for 2 h. Upon cooling, the
resulting mixture was filtered and washed by ethyl acetate
(3 ꢁ 100 mL). The filtrate was concentrated in vacuo to give the
residue, which was directly subjected to flash column chromatography
(EtOAcꢀhexanes, 1:4) to afford O-(2-iodophenyl)-N,N-diethylcarba-
mate as an amber oil (14.8 g, 95% yield). 1H NMR (400 MHz, CDCl3) δ
7.79 (1H, d, J = 8 Hz), 7.31ꢀ7.35 (1H, m), 7.17 (1H, d, J = 8 Hz), 6.92
(1H, t, J = 7.6 Hz), 3.52 (2H, q, J = 6.8 Hz), 3.39 (2H, q, J = 6.8 Hz), 1.32
(3H, t, J = 6.8 Hz), 1.22 (3H, t, J = 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 153.0, 151.7, 139.1, 129.1, 126.8, 123.3, 121.7, 90.8, 42.3, 42.0,
14.3, 13.3.
amber oil (173 mg, 76% yield). IR (film) 2975, 2937, 2901, 2877, 1720,
1683, 1640, 1606, 1579, 1523, 1484, 1432, 1348, 1361, 1314, 1279, 1246,
1
1224, 1106, 1066, 912, 881, 844, 759, 633 cmꢀ1; H NMR (400 MHz,
CDCl3) δ 7.69 (1H, d, J = 8.2 Hz), 7.57 (1H, d, J = 8.2 Hz), 6.97 (1H, s),
3.70 (2H, s), 3.12 (2H, q, J = 7.1 Hz), 3.03 (2H, s), 1.38 (3H, t, J = 7.1 Hz),
1.23 (3H, t, J = 7.2 Hz), 0.98 (3H, t, J = 7.1 Hz), 0.32 (9H, s); 13C NMR
(100 MHz, CDCl3) δ 201.3, 168.1, 166.8, 131.9, 131.0, 123.3, 122.0,
120.4, 115.7, 43.0, 38.9, 33.4, 13.4, 12.5, 8.3, ꢀ2.0; HRMS (FABþ) calcd
for C19H27NO3Si [(M þ H)þ] 346.1838, found 346.1839.
(þ)-(R)-2-Trimethylsilylconcentricolide (8): To a solution of
N,N-diethyl-6-propionyl-2-trimethylsilylbenzofuran-7-carboxamide (7)
(104 mg, 0.30 mmol) and (S)-B-nBu-CBS catalyst19 (0.15 mmol) at 0 °C
with vigorous stirring was added BH3ꢀTHF (1.0 M in THF, 0.45 mL,
0.45 mmol) slowly along the side wall of the reaction flask by a syringe
pump over 5 h. After completion of the addition and another 1 h of
stirring at 0 °C, KOAc (294 mg, 3.0 mmol) and o-xylene (2 mL) were
added to the flask followed by the removal of THF under reduced
pressure. The resulting mixture was directly heated at 140 °C for 1 h.
Upon cooling, water (10 mL) was added and a bilayer solution was then
extracted with EtOAc (3 ꢁ 10 mL). The combined extracts were washed
with brine (5 mL), dried over MgSO4, concentrated, and column
chromatographied (EtOAcꢀhexanes, 1:19) to furnish 2-trimethylsilyl-
N,N-Diethyl-2-hydroxy-3-iodobenzamide (4):18 To a solu-
tion of diisopropylamine (169 μL, 1.20 mmol) in THF (1.2 mL) was
slowly added n-BuLi (2.42 M in n-hexanes, 0.50 mL, 1.21 mmol)
at ꢀ60 °C under nitrogen within 5 min. After the mixture was stirred
for 20 min at ꢀ60 °C, a solution of O-(2-iodophenyl)-N,N-diethylcar-
bamate (3) (319 mg, 1.0 mmol) in THF (1.2 mL) was added within
5 min. The reaction mixture was stirred at ꢀ60 °C for 30 min, then allowed
to warm to room temperature and stirred for another 2 h. The reaction
was quenched with saturated NH4Cl solution (10 mL). After removal of
the organic solvent, the aqueous layer was acidified with 1 N HCl to pH 3
and the resulting residue was extracted with EtOAc (3 ꢁ 30 mL). The
combined extract was washed with brine (10 mL), dried over MgSO4,
and concentrated in vacuo. The residue was purified by flash column
chromatography (EtOAcꢀhexanes, 1:4) to afford N,N-diethyl-2-hydro-
xy-3-iodobenzamide as an amber oil (0.24 g, 72% yield). 1H NMR (400
MHz, CDCl3) δ 9.42 (1H, s), 7.73 (1H, d, J = 7.4 Hz), 7.22 (1H, d,
J = 7.3 Hz), 6.61 (1H, t, J = 7.3 Hz), 3.46 (4H, q, J = 6.7 Hz), 1.22 (6H, t,
J = 6.4 Hz); 13C NMR (100 MHz, CDCl3) δ 170.3, 156.8, 141.3, 127.4,
120.3, 118.8, 86.2, 42.1, 13.2.
concentricolide as a colorless oil (71 mg, 86% yield, 80% ee). [R]25
D
þ13.9 (c 0.92, CHCl3, 80% ee); IR (film) 2966, 2936, 1760, 1635, 1596,
1528, 1462, 1328, 1251, 1283, 1178, 1150, 1109, 1056, 955, 844, 792,
758, 685 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.85 (1H, d, J = 7.9 Hz),
7.21 (1H, d, J = 7.9 Hz), 7.05 (1H, s), 5.54 (1H, dd, J = 7.5, 4.5 Hz),
2.24ꢀ2.06 (1H, m), 1.91ꢀ1.78 (1H, m), 0.99 (1H, t, J = 7.3 Hz), 0.38
(9H, s); 13C NMR (125 MHz, CDCl3) δ 168.2, 166.2, 153.2, 147.9,
129.8, 127.5, 115.8, 115.4, 110.8, 82.6, 27.9, 8.7, ꢀ1.83; HRMS (EIþ) calcd
for C15H18O3Si (Mþ) 274.1025, found 274.1033; enantioselectivity was
determined by HPLC analysis (Chiralpak-AD, 1.0 mL/min, 220 nm,
hexanes/i-PrOH 99/1); retention times were 11.8 (enantiomer) and
13.1 min (major).
(þ)-(R)-Concentricolide (1): To a solution of 2-trimethylsilyl-
concentricolide (8) (63 mg, 0.23 mmol, 80% ee) and AcOH (14 μL,
0.23 mmol) in THF (2 mL) was added tetra-n-butylammonium fluoride
(TBAF, 1 M in THF, 0.25 mL, 0.25 mmol) at room temperature. Upon
completion of the conversion, the resulting solution was concentrated
and purified by flash column chromatography (EtOAcꢀhexanes, 1:9) to
afford concentricolide as a white solid (52 mg, 82% yield, 80% ee). Mp
89ꢀ90 °C (petroleum ether/acetone); mp 116ꢀ117 °C (ethyl acetate/
hexane) [lit. mp 89ꢀ90 °C, petroleum ether/acetone]; [R]25D þ26.1
(c 0.81, CH3OH); IR (film) 2970, 2933, 1761, 1640, 1595, 1536, 1435,
1321, 1204, 1109, 1061, 976, 837, 768, 665 cmꢀ1; 1H NMR (500 MHz,
CDCl3) δ 7.91 (1H, d, J = 8.0 Hz,), 7.80 (1H, d, J = 2.1 Hz), 7.27 (1H, d,
J = 8.0 Hz), 6.90 (1H, d, J = 2.1 Hz), 5.57 (1H, dd, J = 7.0, 4.2 Hz),
2.20ꢀ2.18 (1H, m), 1.86ꢀ1.83 (1H, m), 1.01 (3H, t, J = 7.4 Hz); 1H
NMR (500 MHz, CDOD3) δ 8.02 (1H, d, J = 8.0 Hz), 7.94 (1H, d,
J = 2.2 Hz), 7.41 (1H, d, J = 8.0 Hz), 7.03 (1H, d, J = 2.2 Hz), 5.66 (1H,
dd, J = 6.9, 4.1 Hz), 2.24ꢀ2.17 (1H, m), 1.88ꢀ1.80 (1H, m), 0.95 (3H, t,
J = 7.4 Hz); 13C NMR (125 MHz, CDCl3) δ 168.1, 149.8, 147.9, 146.6,
129.0, 127.9, 116.1, 111.1, 106.6, 82.9, 27.9, 8.8; 13C NMR (125 MHz,
CDOD3) δ 170.1, 151.0, 149.7, 148.1, 130.6, 129.6, 117.6, 111.6, 107.9,
84.7, 28.7, 8.9; HRMS (EIþ) calcd for C12H10O3 (Mþ) 202.0630,
found 202.0633; enantioselectivity was determined by HPLC analysis
(Chiralpak-AD, 1.0 mL/min, 220 nm, hexanes/i-PrOH 99/1); retention
times were 48.7 (major) and 55.4 min (enantiomer).
N,N-Diethyl-2-trimethylsilylbenzofuran-7-carboxamide (6): A
solution of N,N-diethyl-2-hydroxyl-3-iodobenzamide (280 mg, 0.88 mmol),
trimethylsilylacetylene (0.19 mL, 1.32 mmol), and Et3N (0.92 mL, 3.52
mmol) in CH3CN (1.76 mL) in a Schlenk tube was degassed by two
freezeꢀpumpꢀthaw cycles and charged with Pd(PPh3)2Cl2 (6.2 mg,
8.8 μmol) and CuI (1.2 mg, 11.6 μmol) under nitrogen. The resulting
mixture was stirred at 65 °C for 96 h. Upon completion of conversion
1
(monitored by H NMR), the solution was concentrated and directly
purified by flash column chromatography (EtOAcꢀhexanes, 1:9) to afford
N,N-diethyl-2-trimethylsilylbenzofuran-7-carboxamide as an amber oil (223
mg, 88% yield). IR (film) 2965, 2935, 2899, 1633, 1534, 1430, 1481, 1380,
1
1346, 1284, 1250, 1121, 1067, 910, 845, 752, 634 cmꢀ1; H NMR (400
MHz, CDCl3) δ7.57 (1H, dd, J= 7.7, 1.3 Hz,), 7.28 (1H, dd, J= 7.3, 1.3 Hz),
7.21 (1H, t, J=7.5Hz), 6.96(1H, s), 3.66(2H, q,J= 7.1 Hz), 3.20 (2H, q, J=
7.1 Hz), 1.31 (3H, t, J = 7.1 Hz), 1.05 (3H, t, J = 7.1 Hz), 0.32 (s, 8H); 13C
NMR (100 MHz, CDCl3) δ 167.5, 164.1, 153.2, 128.4, 122.9, 122.6, 121.8,
121.4, 116.0, 42.9, 38.9, 14.0, 12.8, ꢀ1.9; HRMS (FABþ) calcd for
C16H23NO2Si [(M þ H)þ] 290.1580, found 290.1576.
N,N-Diethyl-6-propionyl-2-trimethylsilylbenzofuran-7-
carboxamide (7): To a solution of N,N-diethyl-2-trimethylsilylben-
zofuran-7-carboxamide (6) (190 mg, 0.66 mmol) and tetramethylethy-
lenediamine (TMEDA) (156 μL, 1.05 mmol) in THF (2.2 mL)
at ꢀ80 °C was added slowly a solution of t-BuLi (1.44 M in pentane,
0.69 mL, 0.99 mmol). The color of the solution turned to deep-blue
gradually and reached a stable state while the lithiation reagent was
added. The resulting solution was kept at ꢀ80 °C for 1 h and the neat
N-methoxy-N-methylpropionamide (120 mg, 0.99 mmol) was added
slowly at the same temperature. After another 1 h of stirring at ꢀ80 °C,
the reaction was quenched with saturated NH4Cl solution (5 mL). THF
was removed and the residue was diluted with EtOAc (15 mL), washed with
1NHCl(2ꢁ 10 mL) and brine (10 mL), dried over MgSO4, concentrated,
and purified by column chromatography (EtOAcꢀhexanes, 1:4) to afford
N,N-diethyl-6-propionyl-2-trimethylsilylbenzofuran-7-carboxamide as an
(þ)-(R)-2-Bromoconcentricolide (9): To a solution of 2-tri-
methylsilylconcentricolide (8) (106 mg, 0.39 mmol, 80% ee) in CH2Cl2
(3 mL) was added slowly a solution of bromine in CH2Cl2 (0.6 M in
CH2Cl2, 1.3 mL, 0.78 mmol) at room temperature. After 10 min, the
reaction was treated with Et3N (0.2 mL) and concentrated to obtain the
crude product. The residue was purified by flash column chromatography
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NOTE
(CH2Cl2ꢀEtOAcꢀhexanes, 1:1:8) to obtain 2-bormoconcentricolide as
a white solid (84 mg, 77% yield, 80% ee). The solid 2-bormo-
concentricolide with 80% ee was recrystallized three times from
EtOAcꢀhexanes (1:4) to give a colorless needle (48 mg, 58% yield,
>99% ee,). Mp 155ꢀ156 °C; [R]25D þ22.4 (c 0.82, CHCl3); IR (film)
2970, 2931, 1759, 1643, 1538, 1428, 1328, 1299, 1113, 1057, 952, 907,
842 cmꢀ1; 1H NMR (500 MHz, CDCl3) δ 7.80 (1H, d, J = 8.0 Hz), 7.28
(1H, d, J = 8.0 Hz), 6.85 (1H, s), 5.53 (1H, dd, J = 7.0, 4.2 Hz),
2.18ꢀ2.12 (1H, m), 1.83ꢀ1.80 (1H, m), 0.98 (3H, t, J = 7.4 Hz); 13C
NMR (125 MHz, CDCl3) δ 167.3, 150.3, 147.5, 130.2, 130.11, 126.5,
116.8, 110.7, 108.5, 82.8, 27.8, 8.7; HRMS (FABþ) calcd for
C12H9BrO3 [(M þ H)þ] 280.9813, found 280.9814; enantioselectivity
was determined by HPLC analysis (Chiralcel-OJ, 1.0 mL/min, 220 nm,
hexanes/i-PrOH 4/1); retention times were 16.6 (enantiomer) and 25.1
min (major).
Enantiopure (þ)-(R)-Concentricolide (1) Prepared from
2-Bromoconcentricolide (9): Zinc powder (37.5 mg, 0.5 mmol)
was added portionwise to a mixture of 2-bromoconcentricolide (9) (14
mg, 0.05 mmol, >99% ee) in a mixed solvent of AcOH (0.3 mL) and
water (0.1 mL) at 100 °C. After 1 h of heating at 100 °C, the reaction
mixture was cooled to room temperature, filtered, and washed with
EtOAc (3 ꢁ 5 mL). To this filtrate was added saturated NaHCO3
(5 mL) slowly, followed by extraction with EtOAc (2 ꢁ 5 mL). The
combined extracts were washed with brine (5 mL), dried over MgSO4,
and concentrated in vacuo. The residue was purified by column
chromatography (EtOAcꢀhexanes, 1:9) to afford (þ)-concentricolide
(9.6 mg, 95% yield, >99% ee) as a white solid. Mp 89ꢀ90 °C (petroleum
ether/acetone); mp 116ꢀ117 °C (ethyl acetate/hexane); [R]25D þ34.8
(c 0.48, CH3OH); [R]25D þ36.7 (c 0.60, CHCl3).
(7) Ren, J.; Jiang, J.-X.; Li, L.-B.; Liao, T.-G.; Tian, R.-R.; Chen, X.-l.;
Jiang, S.-P.; Pittman, C. U.; Zhu, H.-J. Eur. J. Org. Chem. 2009, 3987.
(8) (a) Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935–1937.
(b) Assimomytis, N.; Sariyannis, Y.; Stavropoulos, G.; Tsoungas, P. G.;
Varvounis, G.; Cordopatis, P. Synlett 2009, 2777.
(9) Hart, D. J.; Mannino, A. Tetrahedron 1996, 52, 3841.
(10) Beak, P.; Snieckus, V. Acc. Chem. Res. 1982, 15, 306.
(11) t-BuLi/TMEDA was found to be the best combination for
lithiation. Either n-BuLi or sec-BuLi with or without TMEDA led to
lower conversion rate.
(12) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(13) For 1H and 13C NMR spectra, see the Supporting Information.
(14) Corey, E. J.; Venkateswarlu, A. J. Am. Chem. Soc. 1972, 94, 6190.
1
(15) The comparison of the H and 13C NMR between synthetic
concentricolide and reported data is summarized in the Supporting
Information. The solvent (CDCl3) used for taking NMR spectra in ref 5
was mistaken for CD3OD.
(16) Shortly before the acceptance of this paper, the natural form
(ꢀ)-(S)-concentricolide [99% ee, mp 87ꢀ88 °C (petroleum ether/
acetone); [R]25 ꢀ35.1 (c 0.48, CH3OH); [R]25 ꢀ37.5 (c 1.0,
D
D
CHCl3)] was synthesized by using the same reagents and procedures
except (R)-CBS catalyst was employed.
(17) García, F.; McPartlin, M.; Morey, J. V.; Nobuto, D.; Kondo, Y.;
Naka, H.; Uchiyama, M.; Wheatley, A. E. H. Eur. J. Org. Chem. 2008, 644.
(18) Miller, R. E.; Rantanen, T.; Ogilvie, K. A.; Groth, U.; Snieckus,
V. Org. Lett. 2010, 12, 2198.
(19) CBS catalyst was prepared according to the procedure reported
in: Chein, R.-J.; Yeung, Y.-Y.; Corey, E. J. Org. Lett. 2009, 11, 1611.
’ ASSOCIATED CONTENT
1
Supporting Information. Copies of H and 13C NMR
S
b
spectra for all new compounds and the X-ray crystallographic
data of (þ)-(R)-concentricolide and compound 9. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rjchein@chem.sinica.edu.tw.
’ ACKNOWLEDGMENT
This research was generously supported by Academia Sinica
and the National Science Council, Taiwan, Republic of China.
We are grateful to the Mass Lab of the Institute of Chemistry,
Academia Sinica for mass analysis and Dr. Yuh-Sheng Wen of
Academia Sinica for taking and processing X-ray data.
DEDICATION
†This paper is dedicated to Professor Tse-Lok Ho on the
occasion of his 73rd birthday.
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